Abstract
Background/Objectives: Atherosclerosis remains a leading cause of morbidity and mortality worldwide, with an urgent need for novel preventive and therapeutic strategies. Sirtuin 1 (SIRT1), an NAD(+)-dependent deacetylase, has emerged as a central regulator of vascular homeostasis, modulating oxidative stress, inflammation, lipid metabolism, and endothelial function. Increasing evidence highlights that some natural activators of SIRT1 may be interesting in mitigating the development of cardiovascular diseases. Methods: Searching in the main databases PubMed and Scopus, we made a literature revision, including studies from January 2000 to June 2025, of the major natural SIRT1 activators involved in vascular impairment in order to investigate their potential therapeutic use in atherosclerosis. Results: Among them, resveratrol, quercetin, naringenin, and hydroxytyrosol show the strongest evidence in activating SIRT1 and modulating the essential molecular pathways involved in atherosclerotic disease. These findings span from preclinical to clinical studies, with limited randomized clinical trial data for hard cardiovascular outcomes. Conclusions: This review synthesizes current knowledge on natural SIRT1 activators in the context of atherosclerosis, emphasizing their molecular mechanisms and clinical perspectives. The concept of using nutraceuticals-based interventions targeting SIRT1 may pave the way for innovative strategies in cardiovascular diseases.